Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]CC.[C:7]([CH:10]1[CH2:14][CH2:13][O:12][C:11]1=[O:15])(=O)[CH3:8].[C:16]([CH:19]1[CH2:23][CH:22]([CH2:24][CH2:25][CH2:26][CH3:27])[O:21][C:20]1=[O:28])(=O)[CH3:17].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:7](=[C:10]1[CH2:14][CH2:13][O:12][C:11]1=[O:15])[CH2:8][CH2:1][CH2:2][CH3:3].[CH:16](=[C:19]1[CH2:23][CH:22]([CH2:24][CH2:25][CH2:26][CH3:27])[O:21][C:20]1=[O:28])[CH2:17][CH2:1][CH2:2][CH3:3]
Reactant: CCCCC=O
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Reactant: CC(=O)C1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCC=C1CC(CCCC)OC1=O
Product: CCCCC=C1CCOC1=O

Procedure:
Two reactions were carried out in accordance with the process of the invention using valeraldehyde. For one reaction (Example VI) 3-acetyl-dihydro-2(3H)-furanone was used and for the second reaction (Example VII) 3-acetyl-5-n-butyldihydro-2(3H)-furanone was employed. Both reactions used sodium hydroxide with toluene as the diluent and the reactants were present in essentially equimolar amounts. 3-Pentylidene-dihydro-2(3H)-furanone (86°-104° C. at 0.1 mm/Hg) and 3-pentylidene-5-n-butyldihydro-2(3H)-furanone (110°-131° C. at 0.01 mm/Hg) were obtained from the respective reactions. Proton nuclear magnetic resonance spectra for the products were as follows:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[S:39](=[O:47])(=[O:46])[N:38]=1.ClCCl.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[S:39](=[O:46])(=[O:47])[N:38]=3)[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC2=NS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (155 mg, 0.384 mmol) and triethylamine (59 μl, 0.423 mmol) in dichloromethane (2 ml) at 0° C., was added a solution of 3-chloro-benzo[d]isothiazole 1,1-dioxide (85.2 mg, 0.423 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was judged complete by tic (dichloromethane/ethyl acetate (1:1)). The reaction mixture was washed with water (3×20 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude residue was subjected to flash chromatography using a gradient from 100% dichloromethane to dichloromethane/ethyl acetate (80/20) as eluent, which afforded 200 mg (92%) of 2-amino-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14](OCC)=[O:15].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:10])[NH:11][C:14](=[O:15])[O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Reaction time: 1 h

Procedure:
1-(3-Chlorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloride-tetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3-chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[N:21]4[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]4=[N:19][C:18]=3[CH:29]3[CH2:31][CH2:30]3)[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N.Cl>C1COCC1>[C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[N:21]4[CH:22]=[CH:23][C:24]([C:26]([NH2:39])=[O:27])=[CH:25][C:20]4=[N:19][C:18]=3[CH:29]3[CH2:31][CH2:30]3)[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4cc(C(=O)O)ccn34)cc2COc2cc(F)ccc21
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4cc(C(N)=O)ccn34)cc2COc2cc(F)ccc21
Temperature: 60 °C
Yield: 86.1 %

Procedure:
[step 6] (E)-3-{[11(6H)-(1-cyanoethylidene)-3-fluorodibenzo[b,e]oxepin-8-yl]methyl}-2-cyclopropylimidazo[1,2-a]pyridine-7-carboxylic acid (2.4 g, 5.1 mmol) obtained in step 5 was suspended in THF (25 mL), 1,1′-carbonyldiimidazole (4.1 g, 25 mmol) was added, and the mixture was stirred with heating at 60° C. for 1.5 hr. To the reaction mixture was added 25% aqueous ammonia solution (4.4 mL, 51 mmol), and the mixture was stirred at room temperature for 15 min. To the mixture was added 2 mol/L hydrochloric acid, and the mixture was stirred at room temperature for 1.5 hr. The precipitated crystals were collected by suction filtration, and dried at 50° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-10/90 v/v) to give the title compound (2.1 g, 86%).
Reaction SMILES: [N+:1]([O-])(O)=O.S(=O)(=O)(O)O.[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>>[CH2:10]1[C:18]2[C:13](=[C:14]([NH2:1])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCC2
Agent: O=S(=O)(O)O
Product: Nc1cccc2c1CCC2
Temperature: 5 °C
Reaction time: 16 h

Procedure:
24 ml (349 mmol) 65% nitric acid are cooled to 0-5° C. 28 ml (518.5 mmol) of concentrated sulphuric acid are slowly added dropwise while cooling with ice. This solution is cooled to 5° C. and slowly added dropwise to 30 ml (232 mmol) indane cooled to 0-5° C., with vigorous stirring and further cooling with ice. The reaction mixture is stirred for 30 min at 0-5° C., and then heated to 25° C. for 1 h with stirring. Then the solution is added dropwise to 150 ml ice/water and stirred for 30 min. The aqueous phase is extracted three times with 200 ml diethyl ether. The combined organic phases are washed twice with 200 ml saturated sodium hydrogen carbonate solution and once with 150 ml distilled water. Then the organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is dissolved in 250 ml of methanol and combined with 4.5 g Raney nickel. The reaction mixture is hydrogenated for 16 h at 3 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:23])=[O:22])[CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of aniline (0.324 ml, 3.55 mmol) in DCM (10 ml) is added pyridine (1.44 ml, 17.76 mmol) followed by a solution of 5-bromo-2-chloro-benzenesulfonyl chloride (1.03 g, 3.55 mmol) in DCM (10 ml). The reaction mixture is stirred at room temperature for 18 hours. DCM (20 ml) is added and the reaction mixture is washed with 2M HCl (50 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:12]([NH2:14])=O)[CH:10]=2)[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:12]#[N:14])[CH:10]=2)[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(N)=O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C#N
Temperature: 130 °C
Yield: 70 %

Procedure:
A mixture of 1-Hydroxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid amide (0.4 g, 1.28 mmol) in POCl3 (10 ml) was sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was poured into ice water, and the precipitate was collected and purified by preparative HPLC to give product (0.28 g, 70%). LC-MS: m/e 314 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11]C)=O)[CH:5]=[N:6][C:7]=1I.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:11])[CH:5]=[N:6][C:7]=1[CH3:13]
Reactant: COC(=O)c1cnc(I)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(C=O)cc1Br
Temperature: 110 °C
Yield: 55.2 %

Procedure:
To a mixture of methyl 5-bromo-6-iodo-3-pyridinecarboxylate (232 mg, 0.679 mmol), tetrakis(triphenylphosphine)palladium (0) (39.2 mg, 0.034 mmol), and K2CO3 (281 mg, 2.036 mmol) in dioxane (5 ml), trimethylboroxin (0.095 ml, 0.679 mmol) was added under N2. The reaction mixture was heated at 110° C. and more tetrakis(triphenylphosphine)palladium (0) was added in several portions until starting material was not detected by HPLC. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude of reaction was purified by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc to afford the title compound (75 mg, 48%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH:9]3[CH2:14][CH:10]3[C:11]=2[NH:12][N:13]=1)=O)C.[OH-].[NH4+:16]>O1CCOCC1>[CH2:14]1[CH:9]2[CH2:8][C:7]3[C:6]([C:4]([NH2:16])=[O:3])=[N:13][NH:12][C:11]=3[CH:10]12
Reactant: CCOC(=O)c1n[nH]c2c1CC1CC21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1n[nH]c2c1CC1CC21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of the ester from Step C (14.2 g, 73.9 mmol) in dioxane (140 mL) was added ammonium hydroxide (28% NH3 in H2O, 750 mL). The mixture was placed in a 1000 mL pyrex bottle and agitated on a shaker plate for 22 h at rt. The mixture was concentrated in vacuo to a total volume of 100 mL at which time a light yellow precipitate was evident. The mixture was filtered and the solid was washed with H2O (2×100 mL). Further drying of the solid in vacuo gave 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide [HPLC/MS: Discovery® C18 column (5μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.09 min, ESI+=164.0 (M+H)] as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(OCC)(=O)C.CCCCC>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]([O:11][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9][O:10][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOc1ccccc1OC(c1ccccc1)C(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OC(c1ccccc1)C(CO[Si](C)(C)C)OS(C)(=O)=O
Temperature: -17 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpropanol from Example 2 (1.44 g, 5 mmole) and triethylamine ((0.77 mL, 5.5 mmole) were dissolved in ethyl acetate (15 mL) and cooled to −17° C. Trimethylsilyl chloride (0.64 mL, 5.0 mmole) dissolved in ethyl acetate (5 mL) was added over 10 minutes keeping the temperature below −15° C. A white precipitate formed during this addition. The mixture was stirred below −15° C. for 15 minutes. Triethylamine (0.8 mL, 5.7 mmole) was added, followed by methanesulfonyl chloride (0.46 mL, 6.0 mmole) dissolved in 5 mL of ethyl acetate, keeping the temperature below −15° C. The mixture was stirred below −15° C. for 15 minutes. Pentane (20 mL) was added and the solids were removed by filtration. The filtrate was concentrated under vacuum to a cloudy oil. The oil was chromatographed on silica (230-400 mesh) eluting with 4:1 heptane-ethyl acetate. The product-containing fractions were concentrated to yield 2.00 g (91.2%) of the title compound as an oil that solidified on standing; mp 80-82.5° C.; 1H NMR (400.13 MHZ, CDCl3) d 0.17 (s, 9H), 1.50 (t, J=6.8 Hz, 3H), 3.06 (s, 3H), 3.77 (dd, J=11, 6, 1H), 4.00 (dd, J=11, 6, 1H), 4.10, (q, J=6.8, 2H), 5.07, (m, 1H), 5.51 (d, J=4.4, 1H), 6.75 (m, 2H), 6.91 (m 2H), 7.2-7.49 (m, 5H); 13C NMR (100.62 MHZ, CDCl3) d 0.0, 15.66, 38.87, 61.57, 64.88, 79.90, 85.20, 113.97, 116.99, 121.32, 122.79, 128.26, 129.09, 129.14, 136.75, 147.72, 149.95; MS (ei) m/e 438.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH2:17])[CH2:12]2)[CH2:7][CH2:6]1.[C:18]([O-:21])([O-])=[O:19].[K+].[K+].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:30]([O:21][C:18](=[O:19])[NH:17][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([N:8]2[CH2:7][CH2:6][N:5]([CH3:4])[CH2:10][CH2:9]2)[CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccccc1
Reactant: CN1CCN([C@@H]2CCC[C@H](N)C2)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN1CCN([C@@H]2CCC[C@H](NC(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
(cis)-3-(4-Methylpiperazin-1-yl)cyclohexanamine trihydrochloride (5.0 g, 16.39 mmol, 1.0 eq.) and K2CO3 (9.05 g, 65.56 mmol, 4.0 eq.) were dissolved in water (15 ml); a solution of Cbz-C1 (2.85 g, 16.39 mmol, 1.0 eq.) in toluene (25 ml) was added at 0° C., and the reaction mixture was then stirred for 16 hours at RT. The reaction solution was diluted with water (15 ml) and the phases were separated. The org. phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Alox, 1% MeOH in DCM). Yield: 37% (2.0 g, 6.04 mmol)
Reaction SMILES: [CH3:1][N+:2]([CH3:4])=[CH2:3].[I-].C(Cl)(=O)C.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>C(#N)C>[CH3:3][N:2]([CH3:4])[CH2:1][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]
Reactant: C=[N+](C)C
Reactant: COc1cccc(C(C)=O)c1
Agent: [I-]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1cccc(C(=O)CCN(C)C)c1
Reaction time: 20.5 h
Yield: 93 %

Procedure:
The Eschenmoser salt was produced by reacting 232 g (2.27 mol, 1 equivalent) tetramethyl diaminomethane with 187 g (2.14 mol, 0.95 equivalent) acetyl chloride in 1200 ml acetonitrile. 328 g (2.17 mol, 0.96 equivalent) 3-methoxyacetophenone were then added within 115 minutes at a temperature of from +3° C. to +11° C. and then stirred at from +20° C. to +25° C. for 20 to 21 hours. The resulting hydrochloride salt of the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) was filtered out. The residue was suspended in 1600 ml water and 190 ml sodium hydroxide solution (36% by weight) (pH 11-12) and extracted with 1000 ml ethyl acetate. The organic phase was separated off and dried over 50 g sodium sulfate. Once the organic solvent had been evaporated, the free base of the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) was obtained as a colorless oil (93% yield, 96% purity ascertained by HPLC).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9].C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[C:8]([O:11][C@@H:12]1[NH:5][C:6](=[O:7])[C@H:13]1[CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCC=COC(C)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC[C@@H]1C(=O)N[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 120 h
Yield: 3.4 %

Procedure:
Eight hundred microliters of chlorosulfonyl isocyanate was added to a solution of 1.28 g (10 mM) pent-1-enyl acetate in 5 ml methylene chloride at 0° under nitrogen. After stirring at 0° 5 days, the reaction mixture was added dropwise to a mixture of 5 g ice, 1.15 ml water, 2.82 g NaHCO3 and 1.0 g Na2SO3 and stirred at 0° for 30 minutes. The mixture was extracted with 2×25 ml methylene choride and the combined organic phases washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel in hexane/ethyl acetate to yield 60 mg trans 4-acetoxy-3-n-propylazetidin-2-one (3.4%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Se](=O)=[O:10]>O1CCOCC1>[CH3:7][C:6]1[O:5][C:4](=[O:8])[O:3][C:2]=1[CH2:1][OH:10]
Reactant: O=[Se]=O
Reactant: Cc1oc(=O)oc1C
Solvent: C1COCCO1
Product: Cc1oc(=O)oc1CO

Procedure:
A mixture of 4,5-dimethyl-2-oxo-1,3-dioxolene (1 mmol) and selenium dioxide (2.5 mmol) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: Rf=0.5, 5% MeOH-dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 42 %

Procedure:
Following general procedure II, (R)-tert-butyl(1-(5-((6-chloro-3-isobutyryl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (225 mg, 0.63 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (175 mg, 0.66 mmol) to afford the desired product (168 mg, 62%) solid: ESI MS m/z 635 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][NH:8][CH:9]=1)=[O:4].[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[OH:11][CH2:10][N:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=[N:8]1
Reactant: COC(=O)c1cn[nH]c1
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1cnn(CO)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
The mixture of 1.40 g of 4-methoxycarbonyl-1H-pyrazole, 0.37 g of paraformaldehyde and 0.11 g of triethylamine was stirred at 130° C. for 1 hour. 0.74 g of paraformaldehyde and 2 ml of triethylamine were added to the mixture and stirred at 130° C. for 2 hours. After the reaction mixture was cooled to room temperature, acetone was added. After the mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.38 g of 1-(hydroxymethyl)-4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[O:19][C:20]([C:23]3[S:24][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=3)=[N:21][N:22]=2)=[CH:13][C:12]=1[CH3:32])[CH2:3]OS(C)(=O)=O.[NH3:33]>C1COCC1.CO>[NH2:33][CH2:3][CH:2]([OH:1])[CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[O:19][C:20]([C:23]3[S:24][C:25]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=3)=[N:21][N:22]=2)=[CH:13][C:12]=1[CH3:32]
Reactant: N
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)COS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CN

Procedure:
A solution of methanesulfonic acid 2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl ester (220 mg, 0.458 mmol) in THF (10 mL) and 7 N NH3 in methanol (10 mL) is stirred at 65° C. for 15 h. The solvent is evaporated and the residue is separated by chromatography on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give 1-amino-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (110 mg) as a yellow oil; LC-MS: tR=0.83 min, [M+1]+=402.48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 509.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C[O:17][C:18]1C=CC=[CH:20][C:19]=1N1CCN(CCCO)CC1>>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:20][CH2:19][CH2:18][OH:17])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Agent: Cl
Product: OCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 82 %

Procedure:
3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]propan-1-ol (36A) is prepared from 1-(2,3-dichloro-phenyl)-piperazine hydrochloride as described for 29A.